Supplement for R01-NS064934 ?Mechanisms of LRRK2 Neurotoxicity? Abstract- LRRK2 in tauopathy Parkinson's disease (PD) and related Lewy body diseases, including dementia with Lewy bodies (DLB), are common causes of Alzheimer's disease related dementias (ADRDs). Although therapies that might slow or halt disease have not been found, recent discoveries from human genetics, post-mortem tissue studies, and disease models have zeroed in on a few genes hypothesized to control disease progression. Tens of thousands of Americans harbor missense mutations in the LRRK2 gene that increase LRRK2 kinase activity and cause PD. Although LRRK2-linked disease is clinically indistinguishable from idiopathic PD, LRRK2 mutation carriers often demonstrate prominent Alzheimer's-type tau pathology, sometimes without traces of alpha-synuclein pathology, in vulnerable regions through the brain. In our ongoing efforts in this project to define the role of LRRK2 in neurodegeneration, we have identified critical interactions between LRRK2 and alpha-synuclein in both neurons and immune cells that both express LRRK2 protein. In this Supplement, we propose the exploration of a direct LRRK2-tau interaction in LRRK2 mediation of Alzheimer's type-tau inclusion spread and neuroinflammation. In supplement to our ongoing work, we will test whether LRRK2 kinase inhibition impairs tau inclusion formation and spread in the brain. In complement to kinase inhibition, we will determine whether LRRK2 kinase activation via genetic mutations in the LRRK2 gene promotes tau inclusions and deleterious pro-inflammatory responses. These studies will help us provide a framework to better understand whether a strong connection exists between LRRK2 and tau pathology found in Alzheimer's disease. Our work may lead to the consideration of tauopathies and Alzheimer's disease (AD) as novel indications for LRRK2-directed therapies.